Cushing's syndrome (CS) is a hormonal disorder caused by prolonged exposure of the body's tissues to high levels of the hormone cortisol. CS in childhood can be caused by genetic forms of bilateral adrenocortical hyperplasia (BAH). Macronodular BAR can be caused by GNAS mutations associated with either McCune-Albright syndrome (MAS) or sporadic adrenal tumors. Micronodular BAH, and its better-known pigmented variant, primary pigmented nodular adrenocortical disease (PPNAD) are caused by germline inactivating mutations of the PRKAR1A gene. Most patients with PPNAD also have Carney Complex (CNC), an autosomal dominant multiple neoplasia syndrome associated with skin lesions, cardiac myxomas, and other non-endocrine and endocrine tumors. In most patients with CNC, the disease is caused by PRKAR1A mutations.
Over the last several years, it has become apparent that there is more than one form of micronodular BAR. Recently, patients were identified with a previously uncharacterized form of micronodular BAH presenting at a young age (Gunther et al., J. Clin. Endocrinol. Metab., 89, 3173-3182 (2004)). Little is known about this newly discovered form of micronodular BAR.
There remains a need for methods, compounds, and compositions that can be used to research, screen for, treat, or prevent Cushing's syndrome and its underlying causes, especially the newly discovered form of micronodular BAH presenting in young children. Such methods, compounds, and compositions are provided herein.